Modulation of the ceramide:glucosylceramide equilibrium by B-cell receptor (BCR) signaling and the novel kinase inhibitors GS-1101 and ibrutinib in CLL. BCR stimulation by antigens (Ags) or anti-IgM results in a shift from ceramide (proapoptotic) to glucosylceramide (antiapoptotic) mediated by up-regulation of UDP-glucose ceramide glucosyltransferase (UGCG). Direct inhibition of UGCG induces chronic lymphocytic leukemia (CLL) cell apoptosis. The kinase-specific inhibitors GS-1101 (PI3K) and ibrutinib (BTK) also cause down-regulation of UGCG leading to restoration of the δ ceramide:glucosylceramide equilibrium and leukemic cell death. This constitutes a novel mechanism of drug action. In addition, this effect on sphingolipid metabolism sensitizes the cells for mitochondria-targeting drugs such as ABT-737. Figure adapted from Schwamb et al; see Figure 6 in the article that begins on page 3978.